Ethanol inhibits luteinizing hormone-releasing hormone (LHRH) secretion by blocking the response of LHRH neuronal terminals to nitric oxide

CANTEROS MARIA GRISELDA; RETTORI, VALERIA; FRANCHI ANA MARIA; GENARO ANA; CEBRAL ELISA; FALETTI ALICIA; GIMENO MARTA; MCCANN SAMUEL

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 1995 vol. 92 p. 3416 - 3420

0027-8424

It has previously been shown that alcohol cansuppress reproduction in humans, monkeys, and small rodentsby inhibiting release of luteinizing hormone (LH). The principalaction is via suppression of the release of LH-releasing hormone(LHRH) both in vivo and in vitro. The present experiments weredesigned to determine the mechanism by which alcohol inhibitsLHRH release. Previous research has indicated that the releaseof LHRH is controlled by nitric oxide (NO). The proposedpathway is via norepinephrine-induced release of NO from NOergicneurons, which then activates LHRH release. In the presentexperiments, we further evaluated the details of this mechanismin male rats by incubating medial basal hypothalamic (MBH)explants in vitro and examining the release ofNO, prostaglandinE2 (PGE2), conversion of arachidonic acid to prostanoids, andproduction of cGMP. The results have provided further supportfor our theory of LHRH control. Norepinephrine increased therelease of NO as measured by conversion of [14C]arginine to[14C]citrulline, and this increase was blocked by the a1 receptorblocker prazosin. Furthermore, the release of LEIRH induced bynitroprusside (NP), a donor of NO, is related to the activation ofsoluble guanylate cyclase by NO since NP increased cGMPrelease from MBHs and cGMP also released LHRH. Ethanolhad no effect on the production of NO by MBH explants or theincreased release of NO induced by norepinephrine. Therefore,it does not act at that step in the pathway. Ethanol also failed toaffect the increase in cGMP induced by NP. On the other hand,as might be expected from previous experiments indicating thatLHRH release was brought about by PGE2, NP increased theconversion of [14C]arachidonic acid to its metabolites, particularlyPGE2. Ethanol completely blocked the release of LHRHIinduced by NP and the increase in PGE2 induced by NP. Therefore,the results support the theory that norepinephrine acts tostimulate NO release from NOergic neurons. This NO diffusesto the LHRH terminals where it activates guanylate cyclase,leading to an increase in cGMP. At the same time, it also activatescyclooxygenase. The increase in cGMP increases intracellularfree calcium, activating phospholipase A2 to provide arachidonicacid, the substrate for conversion by the activated cyclooxygenaseto PGE2, which then activates the release ofLHRH. Since alcoholinhibits the conversion of labeled arachidonic acid to PGE2, itmust act either directly to inhibit cyclooxygenase or perhaps itmay act by blocking the increase in intracellular free calciuminduced by cGMP, which is crucial for activation of both phospholipaseA2 and cyclooxygenase.